Polyphenylene ether resin

ABSTRACT

A poly(phenylene ether) resin composed of structural units represented by the general formula: ##STR1## (wherein R 1 , R 2  and R 3  represent each alkyl, cycloalkyl, etc. or H (provided that two or more of R 1 , R 2  and R 3  do not represent H at the same time), or one of R 1 , R 2  and R 3  represents alkyl or H while the others together form a saturated ring, or R 1 , R 2  and R 3  together form an aromatic ring; A represents alkyl; p is an integer of from 3 to 5; and Y -   represents a pharmaceutically acceptable acid residue) and/or structural units represented by the general formula: ##STR2## (wherein R 4 , R 5  and R 6  represents each alkyl, cycloalkyl, etc. or H (provided that two or more of R 4 , R 5  and R 6  do not represent H at the same time), or one of R 4 , R 5  and R 6  represents alkyl or H while the others together form a saturated ring, or R 4 , R 5  and R 6  together form an aromatic ring; and A, p and Y -   have same meanings as defined above) and structural units represented by the general formula: ##STR3## (wherein R 7  and R 8  represents each alkyl, cycloalkyl, etc. or together form a saturated ring; q is an integer of from 3 to 20; and A, p, and Y -   have same meanings as defined above) wherein the sum of the contents of the structural units represented by the general formula (I) and the structural units represented by the general formula (II) amounts to 40 to 96% by mole and the content of the structural units represented by the general formula (III) amounts to 4 to 60% by mole based upon the content of phenylene ether component and a process for producing the same. The poly(phenylene ether) resins have the effect of adsorbing bile acids and are useful as a cholesterol reducing agent.

TECHNICAL FIELD

The present invention relates to poly(phenylene ether) resins which havethe effect of lowering the level of cholesterol and are useful asmedicaments.

BACKGROUND ART

It is already known that a certain anion exchange resin has the effectof lowering the level of cholesterol in blood and therefore isapplicable as a cholesterol reducing agent (U.S. Pat. Nos. 3,499,960 and3,780,171, U. K. Patent No. 929,391, a published Japanese PatentApplication (Kokai) No. Sho 53-10386). The mechanism by which the levelof cholesterol in blood is lowered by taking the anion exchange resin isconsidered as follows. Namely, the anion exchange resin adsorbs andfixes bile acids in the intestinal tract to prevent the reabsorption ofthe bile acids, and in the liver conversion from cholesterol, which isin an equilibrium relation with bile acids, to bile acids is stimulatedby this action, and consequently, the cholesterol in blood is reduced.

Cholestyramine, a typical anion exchange resin which is used as acholesterol reducing agent, has been employed as an agent for thetreatment of hypercholesterolemia extensively and clinically. However,cholestyramine has the disadvantage that it must be taken in high doses(from 8 to 16 g per day except for excipients) to obtain effectiveaction clinically. Furthermore, cholestyramine is chemical-structurallyunstable and eliminates amines easily because it has quaternary ammoniumgroups at the benzyl position. Accordingly, cholestyramine has a badsmell typical to an aliphatic amine and is difficult to use by itself.Therefore, cholestyramine must be used together with a deodorant or afragrance, or must be used after coating on the surface to reduce thebad smell. In consequence, there remains a problem that it is obliged toincrease the amount of the dosage owing to use of an additive.

DISCLOSURE OF INVENTION

The present invention relates to a poly(phenylene ether) resin composedof structural units represented by the general formula: ##STR4## whereinR¹, R² and R³ are the same or different and each represents an alkylgroup having from 1 to 12 carbon atoms, a cycloalkyl group having from 3to 15 carbon atoms, a cycloalkylalkyl group having from 4 to 15 carbonatoms, an aralkyl group having from 9 to 15 carbon atoms or a hydrogenatom with the proviso that two or more of R¹, R² and R³ do not representa hydrogen atom at the same time, or one of R¹, R² and R³ represents analkyl group having from 1 to 12 carbon atoms or a hydrogen atom whilethe others are adjacent to each other and together form a saturated ringtogether with the nitrogen atom binding to them, which may have one ormore additional hetero atoms, or R¹, R² and R³ are adjacent to eachother and together form an aromatic ring together with the nitrogen atombinding to them, which may have one or more additional hetero atoms; Arepresents an alkyl group having from 1 to 3 carbon atoms; p is aninteger of from 3 to 5; and Y⁻ represents a pharmaceutically acceptableacid residue and/or structural units represented by the general formula:##STR5## wherein R⁴, R⁵ and R⁶ are the same or different and eachrepresents an alkyl group having from 1 to 12 carbon atoms, a cycloalkylgroup having from 3 to 15 carbon atoms, a cycloalkylalkyl group havingfrom 4 to 15 carbon atoms, an aralkyl group having from 9 to 15 carbonatoms or a hydrogen atom with the proviso that two or more of R⁴, R⁵ andR⁶ do not represent a hydrogen atom at the same time, or one of R⁴, R⁵and R⁶ represents an alkyl group having from 1 to 12 carbon atoms or ahydrogen atom while the others are adjacent to each other and togetherform a saturated ring together with the nitrogen atom binding to them,which may have one or more additional hetero atoms, or R⁴, R⁵ and R⁶ areadjacent to each other and together form an aromatic ring together withthe nitrogen atom binding to them, which may have one or more additionalhetero atoms; A represents an alkyl group having from 1 to 3 carbonatoms; p is an integer of from 3 to 5; and Y⁻ represents apharmaceutically acceptable acid residue and structural unitsrepresented by the general formula: ##STR6## wherein R⁷ and R⁸ are thesame or different and each represents an alkyl group having from 1 to 12carbon atoms, a cycloalkyl group having from 3 to 15 carbon atoms, acycloalkylalkyl group having from 4 to 15 carbon atoms or an aralkylgroup having from 9 to 15 carbon atoms, or R⁷ and R⁸ are adjacent toeach other and together form a saturated ring together with the nitrogenatom binding to them, which may have one or more additional heteroatoms; A represents an alkyl group having from 1 to 3 carbon atoms; p isan integer of from 3 to 5; q is an integer of from 3 to 20; and Y⁻represents a pharmaceutically acceptable acid residue wherein the sum ofthe contents of the structural units represented by the general formula(I) and the structural units represented by the general formula (II)amounts to 40 to 96% by mole and the content of the structural unitsrepresented by the general formula (III) amounts to 4 to 60% by molebased upon the content of phenylene ether component, which have theeffect of adsorbing bile acids and are useful as a cholesterol reducingagent, and a process for producing the same.

The present invention relates to a pharmaceutical compositioncomprising, as an active ingredient, the above poly(phenylene ether)resin.

The present invention relates to a cholesterol reducing agentcomprising, as an active ingredient, the above poly(phenylene ether)resin.

The present invention relates to a method for the treatment ofhypercholesterolemia which comprises administering the abovepoly(phenylene ether) resin.

The present invention relates to a use of the above poly(phenylene etherresin for the manufacture a pharmaceutical composition for the treatmentof hypercholesterolemia.

The present invention relates to a use of the above poly(phenyleneether) resin as a cholesterol reducing agent.

BEST MODE FOR CARRYING OUT THE INVENTION

In the above poly(phenylene ether) resins of the present invention, theterm "alkyl group having from 1 to 3 carbon atoms" means a methyl group,an ethyl group, a n-propyl group, an isopropyl group, the term "alkylgroup having from 1 to 12 carbon atoms" means a straight- orbranched-chain alkyl group such as a methyl group, an ethyl group, an-propyl group, an isopropyl group,a n-butyl group, a n-decyl group, an-dodecyl group or the like, the term "cycloalkyl group having from 3 to15 carbon atoms" means a three or more membered saturated cyclic alkylgroup such as a cyclopropyl group, a cyclohexyl group, a cyclododecylgroup or the like, the term "cycloalkylalkyl group having from 4 to 15carbon atoms" means an alkyl group substituted by a three or moremembered saturated cyclic alkyl group such as a cyclopropylmethyl group,a cyclohexylmethyl group, a 2-cyclooctylethyl group, a3-cyclooctylpropyl group, a 3-cyclodecylpropyl group or the like, andthe term "aralkyl group having from 9 to 15 carbon atoms" means an alkylgroup having three or more carbon atoms and substituted by an aryl groupsuch as a 3-phenylpropyl group, a 4-phenylbutyl group, a3-naphthylpropyl group or the like.

Also, the term "saturated ring together with a nitrogen atom binding totwo of R¹, R² and R³, two of R⁴, R⁵ and R⁶ or both of R⁷ and R⁸, whichmay have one or more additional hetero atoms" means a pyrrolidine ring,a piperidine ring, a morpholine ring, a thiomorpholine ring, or thelike.

Also, the term "aromatic ring together with a nitrogen atom binding toall of R¹, R² and R³ or all of R⁴, R⁵ and R⁶, which may have one or moreadditional hetero atoms" means an aromatic ring which may be substitutedby an alkyl group having from 1 to 3 carbon atoms or a cycloalkyl grouphaving from 3 to 15 carbon atoms such as 1-methylimidazole,1-propylimidazole, 1-cyclohexylimidazole, thiazole, 2-methylthiazole orthe like.

Furthermore, the term "pharmaceutically acceptable acid residue" meansan acid residue of a mineral acid such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid or the like, an organic acid suchas methanesulfonic acid, acetic acid, fumaric acid or the like.

The poly(phenylene ether) resins of the present invention can beprepared by the following procedure.

For example, the compounds of the present invention can be prepared bysubjecting a poly 2-(ω-halogenoalkyl)phenylene ether! compoundrepresented by the general formula: ##STR7## wherein X represents achlorine atom, a bromine atom or an iodine atom; n is an integer of from10 to 10,000; and A and p have the same meanings as defined above, whichis dissolved in an organic solvent such as N,N-dimethylformamide,chloroform or toluene, to cross linkage using from 2 to 30 mole % (sumof phenylene ether component of the compound represented by the generalformula (IV) above is 100 mole %) of a diamine compound represented bythe general formula: ##STR8## (wherein R⁷, R⁸ and q have the samemeanings as defined above) in the presence of from 0.1 to 0.2 equivalentvalue of an inorganic base such as potassium carbonate and phasetransfer catalyst such as tetrabutylammonium iodide and in the presenceor absence of γ-cyclodextrin or polyvinylpyrrolidone at from roomtemperature to 120° C., preferably from 40° to 110° C. for from severalhours to several days, occasionally, in a sealed tube and, occasionally,under pressure and an atmosphere of nitrogen, subjecting the resultingcompound to reaction with an amine compound represented by the generalformula: ##STR9## (wherein R¹, R² and R³ have the same meanings asdefined above) at from room temperature to 120° C., preferably from 40°to 110° C. for from several hours to several days, occasionally, in asealed tube and, occasionally, under pressure and an atmosphere ofnitrogen, subjecting, if necessary, the resulting compound to reactionwith an amine compound represented by the general formula: ##STR10##(wherein R⁴, R⁵ and R⁶ have the same meanings as defined above) at fromroom temperature to 120° C., preferably from 40° to 110° C. for fromseveral hours to several days, occasionally, in a sealed tube and,occasionally, under pressure and an atmosphere of nitrogen, andsubjecting, if necessary, the resulting compound to counter ion exchangeusing an appropriate acid and washing, if necessary, the resultingcompound with an appropriate organic solvent, water or the like.

Of the poly(phenylene ether) resins of the present invention,poly(phenylene ether) resins composed of structural units represented bythe general formula: ##STR11## wherein R¹⁵ and R¹⁶ are the same ordifferent and each represents an alkyl group having from 1 to 12 carbonatoms, a cycloalkyl group having from 3 to 15 carbon atoms, acycloalkylalkyl group having from 4 to 15 carbon atoms, an aralkyl grouphaving from 9 to 15 carbon atoms, or R¹⁵ and R¹⁶ are adjacent to eachother and together form a saturated ring together with the nitrogen atombinding to them, which may have one or more additional hetero atoms; R¹⁷represents an alkyl group having from 1 to 12 carbon atoms, a cycloalkylgroup having from 3 to 15 carbon atoms, a cycloalkylalkyl group havingfrom 4 to 15 carbon atoms, an aralkyl group having from 9 to 15 carbonatoms or a hydrogen atom; and A, p and Y⁻ have the same meanings asdefined above and structural units represented by the general formula:##STR12## (wherein R¹⁵, R¹⁶, A, p, q and Y⁻ have the same meanings asdefined above) wherein the content of the structural units representedby the general formula (VIII) amounts to 40 to 96 % by mole and thecontent of the structural units represented by the general formula (IX)amounts to 4 to 60% by mole based upon the content of phenylene ethercomponent can be also prepared by subjecting a poly2-(ω-substituted-aminoalkyl)phenylene ether! compound represented by thegeneral formula: ##STR13## wherein R¹⁵, R¹⁶, A, p and n have the samemeanings as defined above, which is dissolved in an organic solvent suchas N,N-dimethylformamide, chloroform or toluene, to cross linkage usingfrom 2 to 30 mole % (sum of phenylene ether component of the compoundrepresented by the general formula (X) above is 100 mole %) of adihalide compound represented by the general formula:

    X--(CH.sub.2).sub.q --X                                    (XI)

(wherein X and q have the same meanings as defined above) in thepresence of water and in the presence or absence of γ-cyclodextrin orpolyvinylpyrrolidone at from room temperature to 120° C., preferablyfrom 40° to 110° C. for from several hours to several days,occasionally, in a sealed tube and, occasionally, under pressure and anatmosphere of nitrogen, subjecting, if necessary, the resulting compoundto reaction with a halide compound represented by

    R.sup.18 --X                                               (XII)

(wherein R¹⁸ represents an alkyl group having from 1 to 12 carbon atoms,a cycloalkyl group having from 3 to 15 carbon atoms, a cycloalkylalkylgroup having from 4 to 15 carbon atoms or an aralkyl group having from 9to 15 carbon atoms; and X has the same meaning as defined above) at fromroom temperature to 120° C., preferably from 40° to 110° C. for fromseveral hours to several days, occasionally, in a sealed tube and,occasionally, under pressure and an atmosphere of nitrogen, andsubjecting, if necessary, the resulting compound to counter ion exchangeusing an appropriate acid and washing, if necessary, the resultingcompound with an appropriate organic solvent, water or the like.

For example, poly 2-(ω-halogenoalkyl)phenylene ether! compoundsrepresented by the general formula (IV) above which are used as startingmaterials in the aforementioned production process can be prepared bysubjecting a 2-(ω-hydroxyalkyl)phenol compound represented by thegeneral formula: ##STR14## (wherein A and p have the same meanings asdefined above) to polymerization in the presence of from 0.001 to 10mole, preferably from 0.005 to 3 mole of a tertiary amine such aspyridine, triethylamine, triethanolamine andN,N,N',N'-tetramethylethylenediamine to 1 mole of the compoundrepresented by the general formula (XIII) above and from 0.1 to 100 mole%, preferably from 0.5 to 20 mole % of an oxidative catalyst such ascopper(I) chloride, manganese(I) chloride and cobalt (II) chloride andin the presence of a solvent, preferably a hydrocarbon such as tolueneor a mixed solvent of a hydrocarbon such as toluene and an alcohol suchas methanol at from 0° to 40° C., preferably from 10° to 30° C. for from10 minutes to 2 days, preferably from 30 minutes to 24 hours under anatmosphere of oxygen or an air, and subjecting the resulting poly2-(ω-hydroxyalkyl)phenylene ether! compound represented by the generalformula: ##STR15## (wherein A, p and n have the same meanings as definedabove) to halogenation using a halogenating agent such as thionylchloride and carbon tetrabromide-triphenylphosphine.

Of poly 2-(ω-halogenoalkyl)phenylene ether! compounds represented by thegeneral formula (IV) above, poly 2-(ω-chloroalkyl)phenylene ether!compounds where X represents a chlorine atom represented by the generalformula: ##STR16## (wherein A, p and n have the same meanings as definedabove) can be prepared by subjecting a 2-(ω-chloroalkyl)phenol compoundrepresented by the general formula: ##STR17## (wherein A and p have thesame meanings as defined above) to polymerization in the presence offrom 0.001 to 10 mole, preferably from 0.005 to 3 mole of a tertiaryamine such as pyridine, triethylamine, triethanolamine andN,N,N',N'-tetramethylethylenediamine to 1 mole of the compoundrepresented by the general formula (XV) above and from 0.1 to 100 mole%, preferably from 0.5 to 20 mole % of an oxidative catalyst such ascopper (I) chloride, manganese (I) chloride and cobalt (II) chloride andin the presence of a solvent, preferably a hydrocarbon such as tolueneor a mixed solvent of a hydrocarbon such as toluene and an alcohol suchas methanol at from 0° to 40° C., preferably from 10° to 30° C. for from10 minutes to 2 days, preferably from 30 minutes to 24 hours under anatmosphere of oxygen or an air.

Of poly 2-(ω-halogenoalkyl)phenylene ether! compounds represented by thegeneral formula (IV) above, poly(phenylene ether) compounds where Xrepresents a bromine atom or an iodine atom can be also prepared bysubjecting the poly 2-(ω-chloroalkyl)phenylene ether! compoundrepresented by the general formula (IVa) above to halogen exchange usinga haloalkali metal salt such as potassium bromide, sodium bromide,potassium iodide and sodium iodide.

Of poly 2-(ω-halogenoalkyl)phenylene ether! compounds represented by thegeneral formula (IV) above, poly 2-(ω-halogenopropyl)phenylene ether!compounds where q is 3 represented by the general formula: ##STR18##(wherein A, X and n have the same meanings as defined above) can beprepared by subjecting a 2-allylphenol compound represented by theformula: ##STR19## (wherein A has the same meaning as defined above) topolymerization in the presence of from 0.001 to 10 mole, preferably from0.005 to 3 mole of a tertiary amine such as pyridine, triethylamine,triethanolamine and N,N,N',N'-tetramethylethylenediamine to 1 mole ofthe compound represented by the general formula (XVI) above and from 0.1to 100 mole %, preferably from 0.5 to 20 mole % of an oxidative catalystsuch as copper (I) chloride, manganese (I) chloride and cobalt (II)chloride and in the presence of a solvent, preferably a hydrocarbon suchas toluene or a mixed solvent of a hydrocarbon such as toluene and analcohol such as methanol at from 0° to 40° C., preferably from 10° to30° C. for from 10 minutes to 2 days, preferably from 30 minutes to 24hours under an atmosphere of oxygen or an air, subjecting the resultingpoly(2-allylphenylene ether) compound represented by the generalformula: ##STR20## (wherein A and n have the same meanings as definedabove) to reaction with borane-tetrahydrofuran complex, subjecting theresulting compound to treatment with aqueous sodium hydroxide andhydrogen peroxide, and subjecting the resulting poly2-(3-hydroxypropyl)phenylene ether! compound represented by the generalformula: ##STR21## (wherein A and n have the same meanings as definedabove) to halogenation using a halogenating agent such as thionylchloride and carbon tetrabromide-triphenylphosphine.

Of poly 2-(3-halogenopropyl)phenylene ether! compounds represented bythe general formula (IVb) above, poly 2-(3-iodopropyl)phenylene ether!compounds where X is an iodine atom represented by the general formula:##STR22## (wherein A and n have the same meanings as defined above) canbe prepared by subjecting the poly(3-allylphenylene ether) compoundrepresented by the general formula (XVII) above to treatment withzirconocene chloride hydride-iodine.

For example, the poly 2-(ω-substituted-aminoalkyl)phenylene ether!compounds represented by the general formula (X) above which are used asstarting materials in the aforementioned production process can beprepared by subjecting a poly 2-(ω-halogenoalkyl)phenylene ether!compound represented by the general formula (IV) above to reaction withan amine compound represented by the general formula: ##STR23## whereinR15 and R¹⁶ have the same meanings as defined above, or by subjecting a2-(ω-substituted-aminoalkyl)phenol compound represented by the generalformula: ##STR24## (wherein R¹⁵, R¹⁶, A and p have the same meanings asdefined above) to polymerization in the presence of from 0.001 to 10mole, preferably from 0.005 to 3 mole of a tertiary amine such aspyridine, triethylamine, triethanolamine and N,N,N',N'-tetramethylethylenediamine to 1 mole of the compound represented bythe general formula (XIX) above and from 0.1 to 100 mole %, preferablyfrom 0.5 to 20 mole % of an oxidative catalyst such as copper (I)chloride, manganese (I) chloride and cobalt (II) chloride and in thepresence of a solvent, preferably a hydrocarbon such as toluene or amixed solvent of a hydrocarbon such as toluene and an alcohol such asmethanol at from 0° to 40° C., preferably from 10° to 30° C. for from 10minutes to 2 days, preferably from 30 minutes to 24 hours under anatmosphere of oxygen or an air.

For example, the 2-(ω-chloroalkyl)phenol compounds represented by thegeneral formula (XV) above which are used as starting materials in theaforementioned production process can be prepared by subjecting thecorresponding 2-(ω-hydroxyalkyl)phenol compound to chlorination using anappropriate chlorinating agent such as thionyl chloride andmethanesulfonyl chloride.

The compounds represented by the general formulae (V), (VI), (VII),(XI), (XII), (XIII), (XVI), (XVIII) and (XIX) above which are used asstarting materials in the aforementioned production process areavailable commercially, or can be prepared by a process described in aliterature or analogous processes thereto.

In the poly(phenylene ether) resins of the present invention, asexamples of the preferred quaternary ammonium groups, atrimethylammonium group, a dimethylbutylammonium group, adimethylcyclohexylammonium group, a dimethylcyclohexylmethylammoniumgroup and a dimethyl(3-phenylpropyl)-ammonium group are illustrated, andas examples of the preferred tertiary amino groups, a dimethylaminogroup, a cyclohexylmethylamino group, a cyclohexylmethylmethylaminogroup, a butylmethylamino group and a methyl(3-phenylpropyl)-amino groupare illustrated. Examples of the more preferred quaternary ammoniumgroups are a dimethylbutylammonium group and adimethylcyclohexylammonium group.

In the poly(phenylene ether) resins of the present invention, thepreferred length of alkylene chain between the benzene ring and theammonium group, namely, p is 3.

In the poly(phenylene ether) resins of the present invention, thepreferred substituent A is a methyl group.

Furthermore, in the poly(phenylene ether) resins of the presentinvention, as examples of the preferred acid residues, a chlorine ion, abromine ion and a 1/2 sulfate ion are illustrated. The most preferredacid residue is a chlorine ion.

The poly(phenylene ether) resins of the present invention have excellenteffects of adsorbing bile acids. Accordingly, in the in vitro test fordetermination of the bound quantity of bile acids using sodiumglycocholate and sodium taurodeoxycholate, the poly(phenylene ether)resins of the present invention exhibit effects of adsorbing bile acidsequal to or higher than that of cholestyramine (Dowx 1×2 dried resin).In particular, poly(phenylene ether) resins obtained by Examples 5, 6,7, 8, 9, 10, 12, 13, 14, 21, 24, 31, 32, 33 and 34 are preferred.

In the in vivo test for measuring hypocholesterolemic activity usinghamsters (weight: from 75 to 80 g), the poly (phenylene ether) resins ofthe present invention also exhibit markedly more potent cholesterollowering effect than that of cholestyramine (Dowx 1×2 dried resin).Accordingly, serum cholesterol level in two groups (normal diet group,high cholesterol diet group) which were fed a normal diet (CE-2) or anormal diet containing 0.5% cholesterol (high cholesterol diet) for twoweeks was about 200 mg/dl and 300 mg/dl, respectively, and thehypocholesterolemic activities of each resins were compared andestimated as the weight percentage of resin to lower the serumcholesterol level of hamsters fed the high cholesterol diet to that ofhamsters fed the normal diet (EC₁₀₀). As the result, groups which werefed a diet containing from 0.5 to 1% of the poly(phenylene ether) resinof the present invention had serum cholesterol level equal to or lowerthan that of a group which was fed a diet containing 3% ofcholestyramine. In particular, poly(phenylene ether) resins obtained byExamples 33 and 34 exhibit cholesterol lowering effects equal to orhigher than that of cholestyramine at a dose of from 1/5 to 1/4 ofcholestyramine.

When the poly(phenylene ether) resins of the present invention areemployed in the practical treatment, they are administered orally in theform of appropriate pharmaceutical compositions such as tablets,powders, fine granules, granules, capsules, and the like. Thesepharmaceutical compositions can be formulated in accordance withconventional methods using conventional pharmaceutical carriers,excipients and other additives optionally. The poly(phenylene ether)resins of the present invention can be employed as the abovepharmaceutical compositions or the resin alone.

In formulating the pharmaceutical compositions, conventional excipients,disintegrators, binders, lubricants and the like can be used optionally,and, for example, lactose, starch, sodium carboxymethyl starch,povidone, magnesium stearate and polyoxyethylene glycol fatty acid estercan be illustrated.

The dosage is appropriately decided depending on the sex, age, bodyweight, degree of symptoms and the like of each patient to be treated,which is approximately within the range of from 0.1 to 9 g per day peradult human, preferably the range of from 0.1 to 5 g per day per adulthuman, and the daily dosage can be divided into one to several doses perday.

In the case of the oral administration, the poly(phenylene ether) resinsmay be taken in a state suspended in water or other liquid or in a statemixed in food.

EXAMPLE

The present invention is further illustrated in more detail by way ofthe following Reference Examples, Examples and Test Examples.

Reference Example 1 Poly(2-allyl-6-methyl-1,4-phenylene ether)

To benzene (5 L) were added pyridine (162 mL), cuprous chloride (9.9 g),magnesium sulfate (60.2 g) and 2-allyl-6-methylphenol (148.21 g). Afterstirring overnight at 10° C., a solution of methanol and concentratedhydrochloric acid (5:1) was added to the reaction mixture. Theprecipitated polymer was dissolved in chloroform (1 L) and purified bysilica gel chromatography. The resulting polymer was reprecipitated withmethanol, collected by centrifugation and dried to give the titlecompound (110 g).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 2.0-2.2, 3.1-3.3, 4.85-5.1, 5.7-5.9,6.4-6.6

IR (film): 1188, 1469, 1609, 2924 cm⁻¹

Reference Example 2 Poly 2-(3-hydroxypropyl)-6-methyl-1,4-phenyleneether!

To a mechanically stirred solution of borane-tetrahydrofuran complex(900 mL, 1M solution) in tetrahydrofuran (900 mL) was added dropwise asolution of poly(2-allyl-6-methyl-1,4-phenylene ether) (90 g) intetrahydrofuran (900 mL) under ice-cooling. After stirring overnight atroom temperature, a 2N aqueous sodium hydroxide solution (410 mL) and a30% aqueous hydrogen peroxide solution (93 mL) were added to thereaction mixture under ice-cooling. After stirring overnight at roomtemperature, the resulting mixture was washed with brine andcentrifuged. The organic layer was dried over magnesium sulfate andfiltered through Celite®. To the filtrate was added hexane, and theresulting precipitates were collected by filtration and dried to givethe title compound (90 g).

¹ H-NMR (400 MHz, DMSO-d₆) δ ppm: 1.4-1.7, 1.9-2.1, 2.25-2.6, 3.2-3.4,4.3-4.6, 6.4-6.6

IR (film): 1188, 1469, 1602, 2875, 2938, 3100˜3600 cm⁻¹

Reference Example 3 Poly 2-(3-bromopropyl)-6-methyl-1,4-phenylene ether!

To tetrahydrofuran (1.5 L) were added poly2-(3-hydroxypropyl)-6-methyl-1,4-phenylene ether! (82.1 g) andcarbontetrabromide (331.6 g). Triphenylphosphine (144.3 g) dissolved intetrahydrofuran (500 mL) was added dropwise to the mixture. Afterstirring overnight at room temperature, the reaction mixture wasevaporated. The residue was washed with methanol several times,collected by filtration and dried to give the title compound (105.4 g).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.9-2.2, 2.4-2.7, 3.2-3.45, 6.4-6.7

IR (film): 1188, 1469, 1609, 2924, 2959 cm⁻¹

Reference Example 4 Poly 2-(3-iodopropyl)-6-methyl-1,4-phenylene ether!

To a suspension of zirconocene chloride hydride (5.2 g) intetrahydrofuran (20 mL) was added poly 2-allyl-6-methyl-1,4-phenyleneether! (1.0 g). After stirring at room temperature for 1 hour, iodine(5.1 g) was added to the reaction mixture. Then the mixture was stirredat room temperature for 50 minutes and at 50° C. for 15 minutes. Afteraddition of a 1M hydrochloric acid (10 mL), the mixture was stirred for30 minutes. The reaction mixture was extracted with chloroform (500 mL)and a 1M hydrochloric acid (300 mL). The organic layer was washed with a0.5N aqueous sodium thiosulfate solution (500 mL) and brine, dried overmagnesium sulfate and evaporated. The residue was dissolved inchloroform and precipitated with hexane to give the title compound (1.45g).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 2.0-2.2, 2.45-2.65, 3.0-3.2, 6.4-6.7

Reference Example 5 2-(3-Hydroxypropyl)-6-methylphenol

To a borane-tetrahydrofuran complex solution (100 mL, 1M solution) wasadded dropwise 2-allyl-6-methylphenol (21 g) under ice-cooling. Afterstirring at room temperature for 3 hours, a 2N aqueous sodium hydroxidesolution (55 mL) and a 30% aqueous hydrogen peroxide solution (12 mL)were added to the reaction mixture under ice-cooling. After stirringovernight at room temperature, the reaction mixture was acidified with a2N hydrochloric acid and extracted with diethyl ether. The organic layerwas washed with brine, dried over magnesium sulfate, filtered andevaporated. The residue was purified by silica gel column chromatographyand dried to give the title compound (15 g).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.8-1.9(2H, m), 2.2(3H, s), 2.6(¹ H, brs), 2.8(2H, t,

J=6.8 Hz), 3.6(2H, m), 6.7-7.0(4H, m) Mass (FAB⁺, m/z) : 166 (M⁺)

Reference Example 6 Poly 2-(3-hydroxypropyl)-6-methyl-1,4-phenyleneether!

To pyridine (40 mL) were added cuprous chloride (119 mg), magnesiumsulfate (724 mg) and 2-(3-hydroxypropyl)-6-methyl-phenol (2.00 g). Afterstirring overnight at room temperature, the reaction mixture was addedto distilled water, and the resulting precipitates were washed withdistilled water. The precipitates were dissolved in tetrahydrofuran,dried over magnesium sulfate, reprecipitated with hexane, collected byfiltration and dried to give the title compound (1.43 g).

¹ H-NMR (400 MHz, DMSO-d₆) δ ppm: 1.4-1.7, 1.9-2.1, 2.2-2.6, 3.2-3.4,3.8-4.8, 6.4-6.6

IR (film): 1188, 1469, 1602, 2875, 2938, 3100˜3600 cm⁻¹

Reference Example 7 Poly 2-(3-bromopropyl)-6-methyl-1,4-phenylene ether!

To tetrahydrofuran (10 mL) were added poly2-(3-hydroxy-propyl)-6-methyl-1,4-phenylene ether! (0.50 g) andcarbontetrabromide (2.02 g). Triphenylphosphine (880 mg) dissolved intetrahydrofuran (3 mL) was added dropwise to the mixture. After stirringat room temperature for 3 hours, the reaction mixture was evaporated.The residue was washed with methanol several times, collected byfiltration and dried to give the title compound (509 mg).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 2.0-2.2, 2.5-2.65, 3.25-3.4, 6.4-6.6

IR (film): 1188, 1469, 1609, 2959 cm⁻¹

Reference Example 8 Poly 2-3-(N,N-dimethylamino)propyl!-6-methyl-1,4-phenylene ether!

Poly 2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (80 g) wasdissolved in N,N-dimethylformamide (2 L), and a 50% aqueousN,N-dimethylamine solution (100 mL) was added to the solution. Afterstirring at 60° C. for 2 days, the reaction mixture was added dropwiseto a 27% aqueous sodium hydroxide solution (18 L). The resultingprecipitates were collected by filtration, washed with water while beingpulverized in a mortar, collected by filtration and dried to give thetitle compound (84 g).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.6-1.8, 2.0-2.2, 2.4-2.5, 6.4-6.55

IR (film): 1188, 1469, 1602, 2770, 2945 cm⁻¹

Reference Example 9 Poly 2-3-(N,N-dimethylamino)propyl!-6-methyl-1,4-phenylene ether!

To pyridine (20 mL) were added cuprous chloride (51 mg) and 2-3-(N,N-dimethylamino) propyl!-6-methylphenol (1.0 g). After stirring at20° C. for 48 hours, the reaction mixture was evaporated. To the residuewas added a 1N aqueous sodium hydroxide solution (80 mL), and themixture was stirred sufficiently. The resulting precipitates werecollected by filtration, dried and dissolved in methanol (100 mL). Thesolution was filtered through Celite®, and the filtrate was evaporated.The residue was dissolved in methanol (10 mL) and reprecipitated with a1N aqueous sodium hydroxide solution (250 mL). The reprecipitates werecollected by filtration, washed with water and dried to give the titlecompound (762 mg).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.6-1.8, 2.0-2.2, 2.4-2.5, 6.4-6.55

IR (film): 1188, 1469, 1602, 2770, 2945 cm₋₁

Reference Example 10 Poly 2-3-(N,N-dimethylamino)propyl!-6-methyl-1,4-phenylene ether!

To pyridine (20 mL) were added cuprous chloride (51 mg), magnesiumsulfate (0.62 g) and 2- 3-(N,N-dimethylamino)propyl!-6-methylphenol (1.0g). After stirring at 20° C. for 48 hours, the reaction mixture wasevaporated. To the residue was added a 1N aqueous sodium hydroxidesolution (80 mL), and the mixture was stirred sufficiently. Theresulting precipitates were collected by filtration, dried and dissolvedin methanol (100 mL). The solution was filtered through Celite®, and thefiltrate was evaporated. The residue was dissolved in methanol (10 mL)and reprecipitated with a 1N aqueous sodium hydroxide solution (250 mL).The reprecipitates were collected by filtration, washed with water anddried to give the title compound (702 mg).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.6-1.8, 2.0-2.2, 2.4-2.5, 6.4-6.55

IR (film): 1188, 1469, 1602, 2770, 2945 cm⁻¹

Reference Example 11 Poly 2-3-(N-cyclohexyl-N-methylamino)propyl!-6-methyl-1,4-phenylene ether!

To pyridine (20 mL) were added cuprous chloride (51 mg), magnesiumsulfate (0.60 g) and a solution of 2-3-(N-cyclo-hexyl-N-methylamino)propyl!-6-methylphenol (1.0 g) inpyridine (5 mL). After stirring at 20° C. for 48 hours, the reactionmixture was evaporated. To the residue was added a 1N aqueous sodiumhydroxide solution (70 mL), and the mixture was stirred sufficiently.The resulting precipitates were collected by filtration, dried anddissolved in ethanol (100 mL). The solution was filtered throughCelite®, and the filtrate was evaporated. The residue was dissolved inethanol (10 mL) and reprecipitated with a 1N aqueous sodium hydroxidesolution (250 mL). The reprecipitates were collected by filtration,washed with water and dried to give the title compound (75 mg).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 0.9-2.8, 3.0-3.4, 6.3-7.2

IR (film): 1188, 1469, 1659, 2854, 2931 cm⁻¹

Reference Example 12 2-(3-chloropropyl)-6-methylphenol

To a solution of 2-(3-hydroxypropyl)-6-methylphenol (3.0 g) intetrahydrofuran (30 mL) were added pyridine (730 μL), thionyl chloride(2 mL) and one drop of N,N-dimethylformamide. After stirring at 60° C.for 2 hours, the reaction mixture was evaporated, and then diethyl etherwas added to the residue. The resulting solution was washed withdistilled water and brine, dried over anhydrous magnesium sulfate andevaporated in vacuo to give the title compound in quantitative yield.

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 2.09(2H, m), 2.25(3H, s), 2.78(2H, t,J=7.3 Hz), 3.57(2H, t, J=6.4 Hz), 4.70(1H, s), 6.79(1H, t, J=7.5 Hz),6.93-7.05(2H, m)

Reference Example 13 2-(3-Chloropropyl)-6-methylphenol

A solution of N,N-dimethylaniline (24.0 mL) in toluene (20.0 mL) wasbubbled with hydrochloride gas to prepare the correspondinghydrochloride. To the mixture were added2-(3-hydroxypropyl)-6-methylphenol (20.0 g) and methanesulfonyl chloride(10.2 mL), and the resulting mixture was stirred at 110° C. for 1.5hours. After cooling, methanol (2.4 mL) was added to the reactionmixture. The mixture was washed with distilled water, an aqueous sodiumbicarbonate solution, distilled water and brine successively and thenevaporated to give a solution of 2-(3-chloropropyl)-6-methylphenol (19.9g) in toluene (21 g). NMR spectrum of this compound was identical withthat of Reference Example 12.

Reference Example 14 Poly 2-(3-chloropropyl)-6-methyl-1,4-phenyleneether!

To pyridine (1.3 mL) were added cuprous chloride (54 mg) and magnesiumsulfate (130 mg), and the mixture was stirred at room temperature for 10minutes under an atmosphere of oxygen. After addition of2-(3-chloropropyl)-6-methylphenol (1.0 g) to the reaction mixture, themixture was stirred at room temperature for 2 days under an atmosphereof oxygen. After addition of toluene (10 mL) to the reaction mixture,hydrochloride gas was bubbled into the mixture with cooling, and thesupernatant was added to methanol. After the resulting precipitates werepulverized sufficiently, the mixture was stirred for 30 minutes. Theresulting polymer was collected by filtration and dried to give poly2-(3-chloropropyl)-6-methyl-1,4-phenylene ether! (509 mg).

¹ H-NMR (400 MHz, CDCl₃) δ ppm: 1.85-2.3, 2.45-2.8, 3.35-3.65, 6.3-6.65

IR (film): 1188, 1307, 1469, 1602, 2959 cm⁻¹

Reference Example 15 Poly 2-(3-chloropropyl)-6-methyl-1,4-phenyleneether!

To pyridine (44 μL) was added cuprous chloride (54 mg), and the mixturewas stirred at room temperature for 10 minutes under an atmosphere ofoxygen. After addition of 2-(3-chloro-propyl)-6-methylphenol (1.0 g),the mixture was stirred at room temperature for 9 hours under anatmosphere of oxygen. After addition of toluene (5 mL) to the reactionmixture, pyridine was removed in vacuo. After addition of toluene (5 mL)again, hydrochloride gas was bubbled into the mixture with cooling. Thesupernatant was purified by silica gel column chromatography, and thesolution was added to methanol. After the resulting precipitates werepulverized sufficiently, the mixture was stirred for 30 minutes. Theprecipitates were collected by filtration and dried to give poly2-(3-chloro-propyl)-6-methyl-1,4-phenylene ether! (385 mg). NMR spectrumof this compound was identical with that of Reference Example 14.

Reference Example 16 Poly 2-(3-chloropropyl)-6-methyl-1,4-phenyleneether!

To triethylamine (2.27 mL) were added cuprous chloride (54 mg) andmagnesium sulfate (130 mg), and the mixture was stirred at roomtemperature for 10 minutes under an atmosphere of oxygen. After additionof 2-(3-chloropropyl)-6-methylphenol (1.0 g), the mixture was stirred atroom temperature for 18 hours under an atmosphere of oxygen. Afteraddition of toluene (5 mL) to the reaction mixture, triethylamine wasremoved in vacuo. After addition of toluene (5 mL) again, hydrochloridegas was bubbled into the mixture with cooling. The supernatant was addedto methanol, and the precipitated polymer was collected by filtrationand dried to give poly 2-(3-chloro-propyl)-6-methyl-1,4-phenylene ether!(415 mg). NMR spectrum of this compound was identical with that ofReference Example 14.

Reference Example 17 Poly 2-(3-chloropropyl)-6-methyl-1,4-phenyleneether!

To pyridine (1.3 mL) were added cuprous chloride (54 mg) and magnesiumsulfate (130 mg), and the mixture was stirred at room temperature for 10minutes under an air. After addition of2-(3-chloropropyl)-6-methylphenol (1.0 g) to the reaction mixture, themixture was stirred at room temperature for 18 hours under an air. Afteraddition of toluene (5 mL) to the reaction mixture, pyridine was removedin vacuo. After addition of toluene (5 mL) again, hydrochloride gas wasbubbled into the mixture with cooling. The supernatant was added tomethanol, and the precipitated polymer was collected by filtration anddried to give poly 2-(3-chloropropyl)-6-methyl-1,4-phenylene ether!(113mg). NMR spectrum of this compound was identical with that of ReferenceExample 14.

Reference Example 18 Poly 2-(3-chloropropyl)-6-methyl-1,4-phenyleneether!

To pyridine (17.9 mL) was added cuprous chloride (13.2 g), and themixture was stirred at room temperature for 10 minutes under anatmosphere of oxygen. After addition of a solution of2-(3-chloropropyl)-6-methylphenol (73.6 g) in toluene (29 g) obtained bythe similar manner to Reference Example 13, the mixture was stirredovernight at room temperature under an atmosphere of oxygen. Afteraddition of tetrahydrofuran (600 mL) to the reaction mixture, themixture was acidified by bubbling of hydrochloride gas. The solutioncontaining polymer was added to methanol (10 L), and the precipitatedpolymer was dissolved in toluene (500 mL), and the supernatant was addedto methanol (10 L). After the reprecipitates were pulverizedsufficiently, the mixture was stirred for 30 minutes. The reprecipitatedpolymer was collected by filtration and dried to give poly2-(3-chloropropyl)-6-methyl-1,4-phenylene ether! (52.2 g). NMR spectrumof this compound was identical with that of Reference Example 14.

Reference Example 19 Poly 2-(3-chloropropyl)-6-methyl-1,4-phenyleneether!

To toluene (14 mL) were added cuprous chloride (80.5 mg),N,N,N',N'-tetramethylethylenediamine (94.5 mg) andtrimethylstearylammonium chloride (283 mg), and the mixture was stirredat room temperature for 5 minutes under an atmosphere of oxygen. Afteraddition of a solution of 2-(3-chloropropyl)-6-methylphenol (5.00 g) intoluene (5.12 g) obtained by the similar manner to Reference Example 13,the mixture was stirred under an atmosphere of oxygen keeping at 30°-32°C. for 1 hour. When the viscosity of the solution increased, thepolymerization was stopped by the addition of toluene (20 mL), catechol(179 mg), sodium hydrosulfite (283 mg) and water (5 mL). The formedpolymer was precipitated with methanol (800 mL), collected by filtrationand dried to give poly 2-(3-chloropropyl)-6-methyl-1,4-phenylene ether!(4.24 g). NMR spectrum of this compound was identical with that ofReference Example 14.

Reference Example 20 Poly 2-(3-chloropropyl)-6-methyl-1,4-phenyleneether!

To toluene (14 mL) were added cuprous chloride (26.8 mg),N,N,N',N'-tetramethylethylenediamine (40.9 mg) andtrimethylstearylammonium chloride (94.0 mg), and the mixture was stirredat room temperature for 5 minutes under an atmosphere of oxygen. Afteraddition of a solution of 2-(3-chloropropyl)-6-methylphenol (5.00 g) intoluene (5.12 g) obtained by the similar manner to Reference Example 13,the mixture was stirred under an atmosphere of oxygen keeping at 30°-32°C. for 1 hour. When the viscosity of the solution increased, thepolymerization was stopped by the addition of toluene (20 mL), catechol(59.7 mg), sodium hydrosulfite (94.4 mg) and water (5 mL). The formedpolymer was precipitated with methanol (800 mL), collected by filtrationand dried to give poly 2-(3-chloropropyl)-6-methyl-1,4-phenylene ether!(4.07 g). NMR spectrum of this compound was identical with that ofReference Example 14.

Example 1

To N,N-dimethylformamide (1.0 mL) were added poly2-(3-iodopropyl)-6-methyl-1,4-phenylene ether! (0.15 g) and N,N,N',N'-tetramethyl-1,8-diaminooctane (2.2 mg), and the mixture wasstirred at 60° C. for 3 days. After addition ofN,N-dimethylcyclohexylmethylamine (0.78 g), the mixture was stirred at60° C. for 2 days. The reaction mixture was added to acetone, and theresulting precipitates were washed with acetone and then dried to give apoly(phenylene ether) resin (114 mg).

Example 2

To N,N-dimethylformamide (1.0 mL) were added poly 2-3-(N,N-dimethylamino)propyl!-6-methyl-1,4-phenylene ether! (0.20 g),1,8-diiodooctane (6.6 mg) and anhydrous potassium carbonate (0.15 g),and the mixture was stirred at 60° C. for 3 days. After addition ofbromomethylcyclohexane (0.46 g), the mixture was stirred at 60° C. for 2days. The reaction mixture was added to diethyl ether, and the resultingprecipitates were washed with diethyl ether and then dried to give apoly(phenylene ether) resin (104 mg).

Example 3

To N,N-dimethylformamide (2.0 mL) were added poly 2-3-(N,N-dimethylamino)propyl!-6-methyl-1,4-phenylene ether! (0.20 g),1,8-diiodooctane (12 mg) and anhydrous potassium carbonate (0.15 g), andthe mixture was stirred at 60° C. for 3 days. After addition ofbromomethylcyclohexane (0.46 g), the mixture was stirred at 60° C. for 2days. The reaction mixture was added to diethyl ether, and the resultingprecipitates were washed with diethyl ether and then dried to give apoly(phenylene ether) resin (124 mg).

Example 4

To N,N-dimethylformamide (2.0 mL) were added poly 2-3-(N,N-dimethylamino)propyl!-6-methyl-1,4-phenylene ether! (0.20 g),1,8-diiodooctane (26 mg) and anhydrous potassium carbonate (0.15 g), andthe mixture was stirred at 60° C. for 3 days. After addition ofbromomethylcyclohexane (0.46 g), the mixture was stirred at 60° C. for 2days. The reaction mixture was added to diethyl ether, and the resultingprecipitates were washed with diethyl ether and then dried to give apoly(phenylene ether) resin (114 mg).

Example 5

To chloroform (8 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.20 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (3.53 mg) and water (2.5 mL),and the mixture was stirred overnight at 60° C. After addition of a 28%aqueous trimethylamine solution (1.86 mL), the mixture was stirred at60° C. for 2 days. The reaction mixture was evaporated. The residue wasdissolved in a small amount of methanol, precipitated with a 2Nhydrochloric acid and collected by centrifugation. Then, this sequenceof procedure for precipitation was repeated twice, and the obtainedreprecipitates were dried to give a poly(phenylene ether) resin (174mg).

Example 6

To chloroform (10 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.20 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (7.1 mg) and water (2.5 mL), andthe mixture was stirred overnight at 60° C. After addition of a 28%aqueous trimethylamine solution (1.86 mL), the mixture was stirred at60° C. for 2 days. The reaction mixture was evaporated. The residue wasdissolved in a small amount of methanol, precipitated with a 2Nhydrochloric acid and collected by centrifugation. Then, this sequenceof procedure for precipitation was repeated twice, and the obtainedreprecipitates were dried to give a poly(phenylene ether) resin (179mg).

Example 7

To chloroform (410 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (41 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (2.7 g), tetrabutylammoniumiodide (6.6 g), anhydrous potassium carbonate (4.0 g) and water (140mL), and the mixture was stirred overnight at 60° C. After addition of a28% aqueous trimethylamine solution (190 mL), the mixture was stirred at60° C. for 2 days. The reaction mixture was added to acetone, and a 2Nhydrochloric acid was added to the resulting precipitates. The mixturewas stirred for 3 hours, and the precipitates were collected bycentrifugation and dried to give a poly(phenylene ether) resin (30 g).

IR (film): 1188, 1469, 1602, 2938 cm⁻¹

Example 8

To chloroform (3 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (5.6 mg), tetrabutylammoniumiodide (48.8 mg), anhydrous potassium carbonate (30 mg) and water (1.0mL), and the mixture was stirred overnight at 60° C. After addition ofN,N-dimethylcyclohexylamine (504 mg), the mixture was stirred at 60° C.for 2 days. The reaction mixture was evaporated. After the residueswelled in a small amount of methanol, a 2N hydrochloric acid was added,and the mixture was stirred, and the precipitates were collected bycentrifugation. Then, this sequence of procedure for precipitation wasrepeated twice, and the obtained reprecipitates were dried to give apoly(phenylene ether) resin (194 mg).

Example 9

To chloroform (3 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (11.2 mg), tetrabutylammoniumiodide (48.8 mg), anhydrous potassium carbonate (30 mg) and water (1.0mL), and the mixture was stirred overnight at 60° C. After addition ofN,N-dimethylcyclohexylamine (504 mg), the mixture was stirred at 60° C.for 2 days. The reaction mixture was evaporated. After the residueswelled in a small amount of methanol, a 2N hydrochloric acid was added,and the mixture was stirred, and the precipitates were collected bycentrifugation. Then, this sequence of procedure for precipitation wasrepeated twice, and the obtained reprecipitates were dried to give apoly(phenylene ether) resin (209 mg).

Example 10

To chloroform (330 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (35 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (2.3 g), tetrabutylammoniumiodide (5.5 g), anhydrous potassium carbonate (3.3 g) and water (110mL), and the mixture was stirred overnight at 60° C. After addition ofN,N-dimethylcyclohexylamine (57 g), the mixture was stirred at 60° C.for 2 days. The reaction mixture was evaporated. After the residueswelled in a small amount of methanol, a 2N hydrochloric acid was added,and the mixture was stirred, and the precipitates were collected bycentrifugation. Then, this sequence of procedure for precipitation wasrepeated twice, and the obtained reprecipitates were dried to give apoly(phenylene ether) resin (31 g).

IR (film): 1188, 1469, 1602, 2938 cm⁻¹

Example 11

To the poly(phenylene ether) resin (73.8 mg) obtained in Example 3 wasadded a 2N hydrochloric acid (11 mL), and the mixture was stirred atroom temperature for 2 hours. The resulting residue was collected byfiltation and dried in vacuo to give a poly(phenylene ether) resinquantitatively.

Example 12

To chloroform (10 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.20 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (3.53 mg) and water (2.5 mL),and the mixture was stirred at 60° C. for 3 days. After addition ofN,N-dimethylcyclohexylamine (21.5 mg), the mixture was stirred at 60° C.for 2 days. After addition of a 28% aqueous trimethylamine solution(0.56 mL), the mixture was stirred at 60° C. for 2 days. The reactionmixture was evaporated, and 10 mL of methanol was added to the residue.The mixture was added to diethyl ether, and the resulting precipitateswere collected by centrifugation and dried to give a poly(phenyleneether) resin (49 mg).

Example 13

To chloroform (10 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.20 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (7.1 mg) and water (2.5 mL), andthe mixture was stirred at 60° C. for 3 days. After addition ofN,N-dimethylcyclohexylamine (20.6 mg), the mixture was stirred at 60° C.for 2 days. After addition of a 28% aqueous trimethylamine solution(0.56 mL), the mixture was stirred at 60° C. for 2 days. The reactionmixture was evaporated and 10 mL of methanol was added to the residue.The mixture was added to diethyl ether, and the resulting precipitateswere collected by centrifugation and dried to give a poly(phenyleneether) resin (49 mg).

Example 14

To chloroform (400 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (42 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (4.9 g), anhydrous potassiumcarbonate (8.3 g) and water (130 mL), and the mixture was stirred at 60°C. for 3 days. After addition of N,N-dimethylcyclohexylamine (4.70 g),the mixture was stirred at 60° C. for 3 days. After addition of a 28%aqueous trimethylamine solution (157 mL), the mixture was stirred at 60°C. for 4 days. The reaction mixture was allowed to stand, and thechloroform layer was evaporated. The precipitated polymer in the aqueouslayer was collected by centrifugation. The polymer was washed withwater, acetone, a 2N hydrochloric acid, water, acetone and diethyl ethersuccessively, collected by filtration and dried to give a poly(phenyleneether) resin (41.5 g).

Example 15

To chloroform (3 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (22.4 mg), tetrabutylammoniumiodide (48.8 mg), γ-cyclodextrin (300 mg) and water (1.0 mL), and themixture was stirred overnight at 60° C. After addition ofN,N-dimethylcyclohexylamine (504 mg), the mixture was stirred at 60° C.for 2 days. The reaction mixture was added to acetone, and the resultingprecipitates were washed with water. The precipitates were added to a 2Nhydrochloric acid, and the mixture was stirred for 3 hours. Theprecipitates were collected by centrifugation and dried to give apoly(phenylene ether) resin (384 mg).

Example 16

To chloroform (3 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (22.4 mg), tetrabutylammoniumiodide (48.8 mg), polyvinylpyrrolidone (300 mg) and water (1.0 mL), andthe mixture was stirred overnight at 60° C. After addition ofN,N-dimethylcyclohexylamine (504 mg), the mixture was stirred at 60° C.for 2 days. The reaction mixture was added to acetone, and the resultingprecipitates were washed with water. The precipitates were added to a 2Nhydrochloric acid, and the mixture was stirred for 3 hours. Theprecipitates were collected by centrifugation and dried to give apoly(phenylene ether) resin (283 mg).

Example 17

To N,N-dimethylformamide (10 mL) were added poly 2-3-(N,N-dimethylamino)propyl!-6-methyl-1,4-phenylene ether! (0.27 g),1,8-diiodooctane (88 mg) and anhydrous potassium carbonate (27 mg), andthe mixture was stirred at 60° C. for 2 hours. After addition ofiodocyclohexane (1.1 g), the mixture was stirred at 60° C. for 3 days.The reaction mixture was added to diethyl ether, and the resultingprecipitates were collected by centrifugation. After the obtainedprecipitates swelled in N,N-dimethylformamide, the swelling polymer wasreprecipitated with diethyl ether, collected by centrifugation and driedin vacuo to give a poly(phenylene ether) resin (362 mg).

Example 18

To chloroform (3.3 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.35 g),N,N,N',N'-tetramethyl-1,4-diaminobutane (17.3 mg), tetrabutylammoniumiodide (55 mg), anhydrous potassium carbonate (33 mg) and water (1.1mL), and the mixture was stirred overnight at 60° C. After addition ofN,N-dimethylcyclohexylamine (570 mg), the mixture was stirred at 60° C.for 2 days. The resulting precipitates were washed with acetone (40 mL ×2) and a 1N hydrochloric acid (40 mL). Then, the precipitates werewashed with water until the filtrate was neutral, washed with acetoneand dried to give a poly(phenylene ether) resin (366 mg).

Example 19

To chloroform (3.3 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.35 g),N,N,N',N'-tetramethyl-1,12-diaminododecane (17.3 mg), tetrabutylammoniumiodide (55 mg), anhydrous potassium carbonate (33 mg) and water (1.1mL), and the mixture was stirred overnight at 60° C. After addition ofN,N-dimethylcyclohexylamine (570 mg), the mixture was stirred at 60° C.for 2 days. The resulting precipitates were washed with acetone (40 mL ×2) and a 1N hydrochloric acid (40 mL). Then, the precipitates werewashed with water until the filtrate was neutral, washed with acetoneand dried to give a poly(phenylene ether) resin (366 mg).

Example 20

To chloroform (1 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.1 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (6.7 mg), tetrabutylammoniumiodide (16 mg), anhydrous potassium carbonate (9.7 mg) and water (0.5mL), and the mixture was stirred overnight at 60° C. After addition ofan aqueous N,N-dimethylamine solution (50%, 0.4 mL), the mixture wasstirred at 60° C. for 2 days. Chloroform was removed, and the resultingprecipitates were washed with water and dried to give a poly(phenyleneether) resin (86 mg).

Example 21

To chloroform (500 mL) were added poly 2-3-(N,N-dimethyl-amino)propyl!-6-methyl-1,4-phenylene ether! (50 g), asolution of 1,8-diiodooctane (7.7 g) in chloroform (30 mL) and water(250 mL), and the mixture was stirred at 60° C. for 2 days. The reactionmixture was poured into methanol (10 L), and the precipitates werecollected by filtration. After addition of methanol, the precipitateswere sufficiently pulverized in a mortar and then collected byfiltration. After addition of a 1N hydrochloric acid, the precipitateswere sufficiently pulverized in a mortar and then collected byfiltration. The resulting precipitates were washed with a 2Nhydrochloric acid (1 L), water, methanol and diethyl ether successivelyand dried to give a poly(phenylene ether) resin (36.3 g).

IR (KBr) : 1188, 1469, 1602, 2952 cm⁻¹

Example 22

To chloroform (1 mL) were added poly 2-3-(N,N-dimethyl-amino)propyl!-6-methyl-1,4-phenylene ether! (0.1 g),water (0.5 mL) and then a solution of 1,8-diiodooctane (18 mg) inchloroform (0.3 mL) with stirring, and the mixture was stirred overnightat 60° C. The resulting precipitates were washed with methanol anddiethyl ether and dried to give a poly (phenylene ether) resin (70 mg).

Example 23

To chloroform (1 mL) were added poly 2-3-(N,N-dimethyl-amino)propyl!-6-methyl-1,4-phenylene ether! (0.1 g),water (0.5 mL) and then a solution of 1,8-diiodooctane (36 mg) inchloroform (0.3 mL) with stirring, and the mixture was stirred overnightat 60° C. The resulting precipitates were washed with a 1N aqueoussodium hydroxide solution, water, brine, water, methanol and diethylether successively and dried to give a poly(phenylene ether) resin (76mg).

Example 24

To chloroform (1 mL) were added poly 2-3-(N,N-dimethyl-amino)propyl!-6-methyl-1,4-phenylene ether! (0.1 g),water (0.5 mL) and then a solution of 1,8-diiodooctane (36 mg) inchloroform (0.3 mL) with stirring, and the mixture was stirred overnightat 60° C. The resulting precipitates were washed with a 1N hydrochloricacid, water, methanol and diethyl ether successively and dried to give apoly(phenylene ether) resin (82 mg).

Example 25

To chloroform (3.0 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (22.4 mg), tetrabutylammoniumiodide (48.8 mg), anhydrous potassium carbonate (29.2 mg) and water (1.0mL), and the mixture was stirred at 60° C. for 2 days. After addition ofN,N-dimethyl-3-phenylpropylamine (647 mg), the mixture was stirred at60° C. for 2 days. The resulting precipitates were washed with acetone(40 mL × 2) and a 1N hydrochloric acid (40 mL). Then, the precipitateswere washed with water until the filtrate was neutral, washed withacetone and dried to give a poly(phenylene ether) resin (375 mg).

Example 26

To chloroform (3.0 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (22.4 mg), tetrabutylammoniumiodide (48.8 mg), anhydrous potassium carbonate (29.2 mg) and water (1.0mL), and the mixture was stirred at 60° C. for 2 days. After addition ofN-methylimidazole (325 mg), the mixture was stirred at 60° C. for 2days. The resulting precipitates were washed with acetone (40 mL × 2)and 1N hydrochloric acid (40 mL). Then, the precipitates were washedwith water until the filtrate was neutral, washed with acetone and driedto give a poly(phenylene ether) resin (271 mg).

Example 27

To chloroform (1 mL) were added poly 2-3-(N,N-dimethyl-amino)propyl!-6-methyl-1,4-phenylene ether! (0.10 g),water (0.5 mL) and 1,8-diiodooctane (23 mg), and the mixture was stirredovernight at 60° C. for 2 days. The resulting precipitates were washedwith acetone (40 mL × 2), a 1N hydrochloric acid (40 mL) and acetone,and then dried to give a poly(phenylene ether) resin (70.3 mg).

Example 28

To chloroform (3.0 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (22.4 mg), tetrabutylammoniumiodide (48.8 mg), anhydrous potassium carbonate (29.2 mg) and water (1.0mL), and the mixture was stirred at 60° C. for 2 days. After addition ofN,N-dimethylbutylamine (401 mg), the mixture was stirred at 60° C. for 2days. The resulting precipitates were washed with acetone (40 mL × 2)and a 1N hydrochloric acid (40 mL). Then, the precipitates were washedwith water until the filtrate was neutral, washed with acetone and driedto give a poly(phenylene ether) resin (289 mg).

Example 29

To chloroform (3.0 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (22.4 mg), tetrabutylammoniumiodide (48.8 mg), anhydrous potassium carbonate (29.2 mg) and water (1.0mL), and the mixture was stirred at 60 ° C. for 2 days. After additionof N,N-dimethyldodecylamine (845 mg), the mixture was stirred at 60° C.for 2 days. The resulting precipitates were washed with acetone (40 mL ×2) and a 1N hydrochloric acid (40 mL). Then, the precipitates werewashed with water until the filtrate was neutral, washed with acetoneand dried to give a poly(phenylene ether) resin (181 mg).

Example 30

To chloroform (3.0 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (22.4 mg), tetrabutylammoniumiodide (48.8 mg), anhydrous potassium carbonate (29.2 mg) and water (1.0mL), and the mixture was stirred at 60° C. for 2 days. After addition ofN-methylpiperidine (393 mg), the mixture was stirred at 60° C. for 2days. The resulting precipitates were washed with acetone (40 mL × 2)and a 1N hydrochloric acid (40 mL). Then, the precipitates were washedwith water until the filtrate was neutral, washed with acetone and driedto give a poly(phenylene ether) resin (330 mg).

Example 31

To chloroform (3.0 mL) were added poly2-(3-bromopropyl)-6-methyl-1,4-phenylene ether! (0.30 g),N,N,N',N'-tetramethyl-1,8-diaminooctane (22.4 mg), tetrabutylammoniumiodide (48.8 mg), anhydrous potassium carbonate (29.2 mg) and water (1.0mL), and the mixture was stirred at 60° C. for 2 days. After addition ofN,N-dimethylcyclohexylmethylamine (559 mg), the mixture was stirred at60° C. for 2 days. The resulting precipitates were washed with acetone(40 mL × 2) and a 1N hydrochloric acid (40 mL). Then, the precipitateswere washed with water until the filtrate was neutral, washed withacetone and dried to give a poly(phenylene ether) resin (317 mg).

Example 32

To toluene (2.0 mL) were added poly2-(3-chloropropyl)-6-methyl-1,4-phenylene ether! (200 mg),N,N,N',N'-tetramethyl-1,6-diaminohexane (26.5 mg), tetrabutylammoniumiodide (41 mg), anhydrous potassium carbonate (15 mg) and water (0.7mL), and the mixture was stirred at 100° C. for 2 days. After additionof N,N-dimethylbutylamine (334 mg), the mixture was stirred at 100° C.for 2 days. The resulting mixture was washed with acetone (40 mL × 2)and a 2N hydrochloric acid (40 mL × 2). Then, the precipitates werewashed with water until the filtrate was neutral, washed with acetone(40 mL × 2) and dried to give a poly(phenylene ether) resin (210 mg).

Example 33

To toluene (200 mL) were added poly 2-(3-chloropropyl)-6-methylphenyleneether! (20.0 g), N,N,N',N'-tetramethyl-1,6-diaminohexane (2.64 g),tetrabutylammonium iodide (4.04 g), anhydrous potassium carbonate (1.51g) and water (70 mL), and the mixture was stirred at 100° C. for 2 days.After addition of N,N-dimethylbutylamine (33.2 g), the mixture wasstirred at 100° C. for 2 days. The resulting mixture was washed withacetone (750 mL × 2) and a 2N hydrochloric acid (750 mL × 2). Then, theprecipitates were washed with water until the filtrate was neutral,washed with acetone (750 mL × 2) and dried to give a poly(phenyleneether) resin (26.5 g).

Example 34

To toluene (150 mL) were added poly 2-(3-chloropropyl)-6-methylphenyleneether! (15.0 g), N,N,N',N'-tetramethyl-1,6-diaminohexane (1.13 g),tetrabutylammonium iodide (3.03 g), anhydrous potassium carbonate (1.13g) and water (50 mL), and the mixture was stirred at 100° C. for 2 days.After addition of N,N-dimethylcyclohexylamine (31.4 g), the mixture wasstirred at 100° C. for 2 days. The resulting mixture was washed withacetone (500 mL × 2), a 2N hydrochloric acid (1 L) and a 1N hydrochloricacid (1 L). Then, the precipitates were washed with water until thefiltrate was neutral, washed with acetone (500 mL × 2) and dried to givea poly(phenylene ether) resin (14.5 g).

Test Example 1

In vitro test

1) Determination of the bound quantity of bile acids

To a poly(phenylene ether) resin (10 mg) or sea sand (40 mg) as inactivecontrol in a polypropylene tube was added 4.5 ml of a 0.3M phosphatebuffer (pH=6.0) containing 10 mM sodium glycocholate or 15 mM sodiumtaurodeoxycholate. After incubation overnight at room temperature, themixture was centrifuged at 17,000 g for 10 minutes. The quantity of bileacids in the supernatant were determined by enzymatic method(Sotanjusantesutowako made by Wako Pure Chemical Industries, Ltd.), andthe bound quantity of bile acids to the poly (phenylene ether) resin (A)was calculated. The bound quantity of bile acids to the poly(phenyleneether) resin is shown as mmol bile acid/g resin.

2) Determination of the dissociation quantity of bound bile acids

To a bile acid bound poly(phenylene ether) resin or sea sand was added4.5 ml of a 0.3M phosphate buffer (pH=8.0). After incubation at roomtemperature overnight, the mixture was centrifuged at 17,000 g for 10minutes. The quantity of bile acids in the supernatant were determinedby enzymatic method (Sotanjusantesutowako made by Wako Pure ChemicalIndustries, Ltd.), and the dissociation quantity of bile acids fromresin (B) and the dissociation quantity of bile acids from sea sand (C)were calculated.

The dissociation rate was shown as percentage and calculated by thefollowing formula. ##EQU1##

                  TABLE 1    ______________________________________           Bound quantity                         Dissociation rate           (mmol/g resin)                         (%)           sodium sodium     sodium   sodium           glyco- taurodeoxy-                             glyco-   taurodeoxy-           cholate                  cholate    cholate  cholate    ______________________________________    Compound of             2.51     3.61       33     4    Example 7    Compound of             2.57     2.75       29     5    Example 10    Compound of             2.55     3.41       35     9    Example 14    Compound of             2.19     2.17       40     4    Example 21    Compound of             2.36     2.07       28     9    Example 32    Compound of             2.22     3.25       36     5    Example 33    Compound of             2.10     2.54       31     7    Example 34    Dowx 1 × 2             2.28     2.38       49     0    dried resin    ______________________________________

Test Example 2

In vivo test using hamsters

The hypocholesterolemic activity of the poly(phenylene ether) resins ofthe present invention was determined using hamsters. Male hamsters (5weeks, 75-80 g, n=10) were used in this study. A normal diet group wasgiven a normal diet (CE-2 made by Clea Japan, Inc.). A high cholesteroldiet group was given a normal diet containing a 0.5% cholesterol (highcholesterol diet). Test compound diet groups were given a highcholesterol diet containing test compound which was cholestyramine (0.5,1.0, 3.0%, Dowx 1×2 dried resin) or the poly(phenylene ether) resin ofthe present invention (0.25, 0.5, 1.0%). All animals were received thesediets for 14 days and fasted for 24 hours. And then, blood was collectedfrom the abdominal vein to measure serum cholesterol level of eachgroup. Total cholesterol level was enzymatically determined by anautoanalyzer (RA-1000 made by Technicon Co., LTD.). The total serumcholesterol lowering activity by the administration of test compoundswas estimated as follows. Namely, after the inhibition ratio wasdetermined by the following equation, EC₁₀₀ was calculated as the weightpercentage of resin to the diet to lower the serum cholesterol level(about 300 mg/dl) of hamsters fed the high cholesterol diet to that(about 200 mg/dl) of hamsters fed the normal diet. The following tableindicates EC₁₀₀ of cholestyramine and the poly(phenylene ether) resinsof the present invention. Thus, the poly(phenylene ether) resins of thepresent invention had cholesterol lowering effect equal to or higherthan that of cholestyramine at a dose of from 1/5 to 1/4 ofcholestyramine.

Inhibition ratio (%)= 1-(s--n)/(c--n)!×100

s:Total serum cholesterol level of test compound diet group

n:Total serum cholesterol level of normal diet group

c:Total serum cholesterol level of high cholesterol diet group

                  TABLE 2    ______________________________________                 EC.sub.100 (%)    ______________________________________    Dowx 1 × 2                   2.8    dried resin    Compound of    0.5    Example 33    Compound of    0.7    Example 34    ______________________________________

Industrial Applicability

The poly(phenylene ether) resins of the present invention arecharacteristic of possessing ω-ammoniumalkyl groups where length ofalkylene chain between the benzene ring and the ammonium group is threeor more and remarkable effect of adsorbing bile acids. Furthermore, thepoly(phenylene ether) resins of the present invention have no aminesmell due to degradation of amine part and extreme stability. Inaddition, the poly(phenylene ether) resins of the present invention areinsoluble in water because of crosslinkage at the position of theammonium group, and therefore have high safety. Accordingly, thepoly(phenylene ether) resins of the present invention are useful as anexcellent medicament for a cholesterol lowering agent.

We claim:
 1. A poly(phenylene ether) resin composed of structural unitsrepresented by the general formula: ##STR25## wherein R¹, R² and R³ arethe same or different and each represents an alkyl group having from 1to 12 carbon atoms, a cycloalkyl group having from 3 to 15 carbon atoms,a cycloalkylalkyl group having from 4 to 15 carbon atoms, an aralkylgroup having from 9 to 15 carbon atoms or a hydrogen atom provided thattwo or more of R¹, R² and R³ do not represent a hydrogen atom at thesame time, or one of R¹, R² and R³ represents an alkyl group having from1 to 12 carbon atoms or a hydrogen atom while the others are adjacent toeach other and together form a saturated ring together with the nitrogenatom binding to them, which may have one or more additional heteroatoms, or R¹, R² and R³ are adjacent to each other and together form anaromatic ring together with the nitrogen atom binding to them, which mayhave one or more additional hetero atoms; A represents an alkyl grouphaving from 1 to 3 carbon atoms; p is an integer of from 3 to 5; and Y⁻represents a pharmaceutically acceptable acid residue and structuralunits represented by the general formula: ##STR26## wherein R⁷ and R⁸are the same or different and each represents an alkyl group having from1 to 12 carbon atoms, a cycloalkyl group having from 3 to 15 carbonatoms, a cycloalkylalkyl group having from 4 to 15 carbon atoms or anaralkyl group having from 9 to 15 carbon atoms, or R⁷ and R⁸ areadjacent to each other and together form a saturated ring together withthe nitrogen atom binding to them, which may have one or more additionalhetero atoms; A represents an alkyl group having from 1 to 3 carbonatoms; p is an integer of from 3 to 5; q is an integer of from 3 to 20;and Y⁻ represents a pharmaceutically acceptable acid residue wherein thecontent of the structural units represented by the general formula (I)amounts to 40 to 96% by mole and the content of the structural unitsrepresented by the general formula (III) amounts to 4 to 60% by molebased upon the content of the phenylene ether component.
 2. Apoly(phenylene ether) resin as claimed in claim 1, composed ofstructural units represented by the general formula: ##STR27## whereinR⁹, R¹⁰ and R¹¹ are the same or different and each represents an alkylgroup having from 1 to 12 carbon atoms, a cycloalkyl group having from 3to 15 carbon atoms, a cycloalkylalkyl group having from 4 to 15 carbonatoms, an aralkyl group having from 9 to 15 carbon atoms or a hydrogenatom provided that two or more of R⁹, R¹⁰ and R¹¹ do not represent ahydrogen atom at the same time, or one of R⁹, R¹⁰ and R¹¹ represents analkyl group having from 1 to 12 carbon atoms or a hydrogen atom whilethe others are adjacent to each other and together form a saturated ringtogether with the nitrogen atom binding to them, which may have one ormore additional hetero atoms; A represents an alkyl group having from 1to 3 carbon atoms; p is an integer from 3 to 5; and Y⁻ represents apharmaceutically acceptable acid residue and structural unitsrepresented by the general formula: ##STR28## wherein R⁷, and R⁸ are thesame or different and each represents an alkyl group having from 1 to 12carbon atoms, a cycloalkyl group having from 3 to 15 carbon atoms, acycloalkylalkyl group having from 4 to 15 carbon atoms or an aralkylgroup having from 9 to 15 carbon atoms, or R⁷ and R⁸ are adjacent toeach other and together form a saturated ring together with the nitrogenatom binding to them, which may have one or more additional heteroatoms; A represents an alkyl group having from 1 to 3 carbon atoms; p isan integer of from 3 to 5; q is an integer of from 3 to 20; and Y⁻represents a pharmaceutically acceptable acid residue wherein thecontent of the structural units represented by the general formula (Ia)amounts to 40 to 96% by mole and the content of the structural unitsrepresented by the general formula (III) amounts to 4 to 60% by molebased upon the content of the phenylene ether component.
 3. Apoly(phenylene ether) resin as claimed in claim 2, composed ofstructural units represented by the general formula: ##STR29## whereinR¹⁹ represents a cyclohexyl group or a n-butyl group and structuralunits represented by the general formula: ##STR30## wherein q is aninteger of from 3 to 20 wherein the content of the structural unitsrepresented by the general formula (VIIIa) amounts to 40 to 96% by moleand the content of the structural units represented by the generalformula (IXa) amounts to 4 to 60% by mole based upon the content of thephenylene ether component.
 4. A process for production of thepoly(phenylene ether) resin as claimed in claim 2, which comprisessubjecting a poly(phenylene ether) compound represented by the generalformula: ##STR31## wherein R¹⁵ and R¹⁶ are the same or different andeach represents an alkyl group having from 1 to 12 carbon atoms, acycloalkyl group having from 3 to 15 carbon atoms, a cycloalkylalkylgroup having from 4 to 15 carbon atoms or an aralkyl group having from 9to 15 carbon atoms, or R¹⁵ and R¹⁶ are adjacent to each other andtogether form a saturated ring with the nitrogen atom binding to them,which may have one or more additional hetero atoms; A represents analkyl group having from 1 to 3 carbon atoms; p is an integer of from 3to 5; and n is an integer of from 10 to 10,000, to crosslinking using adihalide compound represented by the general formula:

    X--(CH.sub.2).sub.q --x

wherein X represents a chlorine atom, a bromine atom or an iodine atom;and q is an integer of from 3 to 20, and optionally subjecting theresulting compound to reaction with a halide compound represented by thegeneral formula:

    R.sup.18 --X

wherein R¹⁸ represents an alkyl group having from 1 to 12 carbon atoms,a cycloalkyl group having from 3 to 15 carbon atoms, a cycloalkylalkylgroup having from 4 to 15 carbon atoms or an aralkyl group having from 9to 15 carbon atoms; and X represents a chlorine atom, a bromine atom oran iodine atom.
 5. A poly(phenylene ether) resin obtained by a processwhich comprises subjecting a poly(phenylene ether) compound representedby the general formula: ##STR32## wherein A represents an alkyl grouphaving from 1 to 3 carbon atoms; X represents a chlorine atom, a bromineatom or an iodine atom; p is an integer of from 3 to 5; and n is aninteger of from 10 to 10,000, to crosslinking using a diamine compoundrepresented by the general formula: ##STR33## wherein R⁷ and R⁸ are thesame or different and each represents an alkyl group having from 1 to 12carbon atoms, a cycloalkyl group having from 3 to 15 carbon atoms, acycloalkylalkyl group having from 4 to 15 carbon atoms or an aralkylgroup having from 9 to 15 carbon atoms, or R⁷ and R⁸ are adjacent toeach other and together form a saturated ring together with the nitrogenatom binding to them, which may have one or more additional heteroatoms; and q is an integer of from 3 to 20, and subjecting the resultingcompound to reaction with one or two amine compounds represented by thegeneral formula: ##STR34## wherein R¹, R² and R³ are the same ordifferent and each represents an alkyl group having from 1 to 12 carbonatoms, a cycloalkyl group having from 3 to 15 carbon atoms, acycloalkylalkyl group having from 4 to 15 carbon atoms, an aralkyl grouphaving from 9 to 15 carbon atoms or a hydrogen atom provided that two ormore of R¹, R² and R³ do not represent a hydrogen atom at the same time,or one of R¹, R² and R³ represents an alkyl group having from 1 to 12carbon atoms or a hydrogen atom while the others are adjacent to eachother and together form a saturated ring together with the nitrogen atombinding to them, which may have one or more additional hetero atoms, orR¹, R² and R³ are adjacent to each other and together form an aromaticring with the nitrogen atom binding to them, which may have one or moreadditional hetero atoms.
 6. A poly(phenylene ether) resin obtained bythe process as claimed in claim 4, which comprises subjecting apoly(phenylene ether) compound represented by the general formula:##STR35## wherein R¹⁵ and R¹⁶ are the same or different and eachrepresents an alkyl group having from 1 to 12 carbon atoms, a cycloalkylgroup having from 3 to 15 carbon atoms, a cycloalkylalkyl group havingfrom 4 to 15 carbon atoms or an aralkyl group having from 9 to 15 carbonatoms, or R¹⁵ and R¹⁶ are adjacent to each other and together form asaturated ring with the nitrogen atom binding to them, which may haveone or more additional hetero atoms; A represents an alkyl group havingfrom 1 to 3 carbon atoms; p is an integer of from 3 to 5; and n is aninteger of from 10 to 10,000, to crosslinking using a dihalide compoundrepresented by the general formula:

    X--(CH.sub.2).sub.q --X

wherein X represents a chlorine atom, a bromine atom or an iodine atom;and q is an integer of from 3 to 20, and optionally subjecting theresulting compound to reaction with a halide compound represented by thegeneral formula:

    R.sup.18 --X

wherein R¹⁸ represents an alkyl group having from 1 to 12 carbon atoms,a cycloalkyl group having from 3 to 15 carbon atoms, a cycloalkylalkylgroup having from 4 to 15 carbon atoms or an aralkyl group having from 9to 15 carbon atoms; and X represents a chlorine atom, a bromine atom oran iodine atom.
 7. A pharmaceutical composition comprising, as an activeingredient, a poly(phenylene ether) resin as claimed in claim 1,composed of structural units represented by the general formula:##STR36## wherein R¹, R² and R³ are the same or different and eachrepresents an alkyl group having from 1 to 12 carbon atoms, a cycloalkylgroup having from 3 to 15 carbon atoms, a cycloalkylalkyl group havingfrom 4 to 15 carbon atoms, an aralkyl group having from 9 to 15 carbonatoms or a hydrogen atom provided that two or more of R¹, R² and R³ donot represent a hydrogen atom at the same time, or one of R¹, R² and R³represents an alkyl group having from 1 to 12 carbon atoms or a hydrogenatom while the others are adjacent to each other and together form asaturated ring together with the nitrogen atom binding to them, whichmay have one or more additional hetero atoms, or R¹, R² and R³ areadjacent to each other and together form an aromatic ring together withthe nitrogen atom binding to them, which may have one or more additionalhetero atoms; A represents an alkyl group having from 1 to 3 carbonatoms; p is an integer of from 3 to 5; and Y⁻ represents apharmaceutically acceptable acid residue and structural unitsrepresented by the general formula: ##STR37## wherein R⁷ and R⁸ are thesame or different and each represents an alkyl group having from 1 to 12carbon atoms, a cycloalkyl group having from 3 to 15 carbon atoms, acycloalkylalkyl group having from 4 to 15 carbon atoms or an aralkylgroup having from 9 to 15 carbon atoms, or R⁷ and R⁸ are adjacent toeach other and together form a saturated ring together with the nitrogenatom binding to them, which may have one or more additional heteroatoms; A represents an alkyl group having from 1 to 3 carbon atoms; p isan integer of from 3 to 5; q is an integer of from 3 to 20; and Y⁻represents a pharmaceutically acceptable acid residue wherein thecontent of the structural units represented by the general formula (I)amounts to 40 to 96% by mole and the content of the structural unitsrepresented by the general formula (III) amounts to 4 to 60% by molebased upon the content of the phenylene ether component.
 8. Apharmaceutical composition comprising, as an active ingredient, apoly(phenylene ether) resin as claimed in claim 3, composed ofstructural units represented by the general formula: ##STR38## whereinR¹⁹ represents a cyclohexyl group or a n-butyl group and structuralunits represented by the general formula: ##STR39## wherein q is aninteger of from 3 to 20 wherein the content of the structural unitsrepresented by the general formula (VIIIa) amounts to 40 to 96% by moleand the content of the structural units represented by the generalformula (IXa) amounts to 4 to 60% by mole based upon the content ofphenylene ether component.
 9. A cholesterol reducing agent comprising,as an active ingredient, the poly(phenylene ether) resin as claimed inclaim
 1. 10. A cholesterol reducing agent comprising, as an activeingredient, the poly(phenylene ether) resin as claimed in claim
 3. 11. Amethod for the treatment of hypercholesterolemia which comprisesadministering an effective amount of the poly(phenylene ether) resin asclaimed in claim
 1. 12. A method for the treatment ofhypercholesterolemia which comprises administering an effective amountof the poly(phenylene ether) resin as claimed in claim 3.